Aqueous injectable formulations useful for radiodiagnosis comprising iodinated aromatic compounds used as X-ray contrast media

ABSTRACT

This invention refers to injectable aqueous formulations containing radiopaque contrast agents useful for X-ray imaging of human or animal body. This invention specially deals with injectable aqueous solutions of mixtures of non-ionic and water-soluble iodinated aromatic compounds preferably constituted by: a) compounds comprising an aromatic nucleus at least triiodo-substituted; b) compounds comprising at least two aromatic nuclei variably bound together, each one at least triiodo substituted.

FIELD OF THE INVENTION

This invention refers to injectable aqueous formulations containingradiopaque contrast agents useful for X-ray imaging of human or animalbody.

One of the preferred aspects of this invention specially deals withinjectable aqueous solutions of mixtures of non-ionic and water-solubleiodinated aromatic compounds preferably constituted by:

a) compounds comprising an aromatic nucleus at leasttriiodo-substituted--from now on referred to as monomers or monomeric,

b) compounds comprising at least two aromatic nuclei variably boundtogether, each one at least triiodo substituted--from now on referred toas dimers or dimeric.

Beyond the compounds of type a) and b), this invention also includesother possible mixtures comprising opacifying derivatives with molecularstructures of three or more polyiodinated aromatic nuclei.

BACKGROUND OF THE INVENTION

Formulations containing X-ray contrast agents (CM) have long been usedto enhance the image contrast of human and animal cavities in X-rayexaminations. Among the past radiopaque products which have beeninvestigated, it is worth mentioning derivatives of elements such as Ba,Bi, Ta. But afterwards it was found that certain classes ofwater-soluble brominated and/or iodinated organic compounds are fargreatly useful as contrast agents for the vascular system.

2,4,6-triiodo-benzene derivatives are commonly used as iodinatedaromatic X-ray-opaque compounds since their remaining positions 1,3,5are substituted by suitable organic substituents to reach a sufficientwatersolubility, a iodine concentration of 300-450 g/L or more, and agood tolerability.

A good solubility, for example, can be obtained through the introductionon the aromatic nucleus of carboxylic functions which can be salified.These compounds are the so-called ionic iodinated contrast agents. Atypical example is the diatrizoic acid(3,5-diacetamido-2,4,6-triiodobenzoic acid) and its meglumine salt,particularly used in angiography. It is highly water-soluble and has arelatively low molecular weight. These features allow injectablesolutions with a high iodine content and a low viscosity, essential fora good vascular X-ray imaging.

Unfortunately, ionic contrast media solutions show a high toxicity.Furthermore they are hyperosmotic to plasma (the presence of ionsconsiderably increases osmolality and therefore the osmotic pressurewhen compared to other physiological fluids), causing possible painfuleffects in patients after injection. Other drawbacks related to ioniccontrast agents rely on the presence of massive counter-cationconcentrations (Na⁺, Ca2⁺ and others): the consequence is an increase inthe osmotic load, that's to say the amount of administered osmoles, prodose. It is known that a high osmotic load causes a toxicity increase.Moreover cardiovascular effects may occur as a result of the increase inplasma volume.

To overcome this problem, non-ionic iodinated agents have beendeveloped, where the substituents on the aromatic nucleus have noionizable functions. In this case a sufficient water-solubility isgranted by highly hydrophilic neutral groups in positions 1,3,5 of thearomatic nucleus. Non-limiting examples of compounds belonging to thislast mentioned class of opacifying agents are given by "iopamidol"(BRACCO), or N,N'-bis-2-hydroxy-1-(hydroxymethyl)ethyl!-2,4,6-triiodo-5-lactamido-isophthalamide,and "iomeprol" (BRACCO) orN,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-5-(N-methyl-hydroxyacetylamino)-isophthalamide.

Disregarding the improvements obtained on non-ionic aromatictriiodo-derivatives, there was still the need of decreasing theosmolality in the corresponding opacifying injectable formulations inorder to obtain an osmotic pressure more similar to blood. Osmolality isthe common term used to relate molality to osmotic pressure. In fact,highly concentrated solutions of different iododerivatives, can showosmolality values that are too high to be tolerable by the human body.By way of an example, a 1 osmol/kg. H₂ O (=1000 mosmol/kg) solution cangenerate a 25.5-atm or 2.58-MPa osmotic pressure, hence aphysiologically unacceptable value. A way to decrease osmolality, bykeeping the total iodine content of aqueous solutions between a desiredrange, is favouring molecular aggregation. Another way consists inincreasing the number of atoms of iodine per molecule, for instance bycovalently binding together two or more triiodinated aromatic nucleithrough suitable alkylenic bridges, functionally substituted or not, toobtain the so-called oligomeric or dimeric structures. However in thiscase, the viscosity of said compounds usually reaches values scoringmore than 8-14 mPa7s. This range is generally considered the highestacceptable limit for catheter administrations of opacifying solutions ata rate compatible with the vascular system imaging.

Referring, to the above mentioned problems, a wide bibliographicdocumentation is available comprising technical articles, patents andbooks. Quite useful documents can be: "X-Ray Contrast Media", by U.Speck published by Medical Division, Department of Medical Information,Schering AG (DE); D. P. Swanson et al., "Pharmaceuticals in MedicalImaging" (1990) Mc Millan Publ. Co.; "Radiocontrast Agents", by M.Sovak, published by Springer Verlag (1984), M. Elke et al.,"Kontrastmittel in der radiologischen Diagnostik", G. Thieme VerlagStuttgart, New York (1992).

Table 1 reports data, disclosed in the prior art, of some well-knowniodinated contrast agents, considering the corresponding osmolality andviscosity values of their aqueous solutions according to certain iodineconcentrations. Letters i, ni, m, d, stand for compound structuralcharacteristics (i--ionic; ni--non ionic; m--monomer; d--dimer).

                                      TABLE 1                                     __________________________________________________________________________    Compound or medium     Osmolality H.sub.2 O                                                                  Viscosity at 37° C.                     solution    Structure                                                                          Iodine (g/L)                                                                        mosmol/kg                                                                             (mPa · s)                             __________________________________________________________________________    Blood       --   --    290     4                                              diatrizoate (meglumine)                                                                    i m 282   1500    4                                              ioxaglate    i d 320   580     7.5                                            iopromide   ni m 300   630     4.6                                            iopamidol   ni m 300   620     4.5                                            iomeprol    ni m 300   521     4.5                                            iohexol     ni m 300   690     6.1                                            metrizamide ni m 300   485     6.2                                            ioversol    ni m 320   702     5.8                                            iogulamide  ni m 300   1040    9.6                                            iodixanol   ni d 300   200     8.7                                            iodecol     ni d 300   320     7.2                                            iotrol      ni d 300   320     8.1                                            iofratol    ni d 300   141     8.5                                            EP-23992 B  ni d 300   184     7.4                                            (compound A, Ex. 15)                                                          __________________________________________________________________________

The data of Table 1 show that, osmolality levels are still too high ifcompared to blood (about 300 mosmol/kg), despite the shift from ionic tonon-ionic contrastographic compounds which remarkably reduces theinjectable solution osmolality if a iodine concentration of about 300g/L is used. A way to further reduce osmolality, down to the blood valueor even lower values, is using iodinated compounds such as dimers. But,on the other hand, viscosity is too high for most of diagnosticapplications requiring quick injections of opacifying formulations intothe vascular system. It is worth remembering that in the X-ray vascularimaging, iodine delivery rate is very important. The rate is expressedin grams of iodine per second at 370C. g(iodine)/s!, meanwhile theinjection pressure through less invasive catheters (i.e. Cordis.4F) isof about 61.2 atm or 6.20 MPa. Obviously, iodine delivery rate dependson the solution concentration and on the volumetric flow rate, which isconnected to viscosity and the kind of flow.

Furthermore, in some cases, dimeric solutions are hypotonic and thisrequires a salt addition to their formulations to reach the isotonicitywith blood.

Patent application GB-A-2050167 (Mallinckrodt) claims that it ispossible obtaining X-ray opacifying compositions that, at a iodineconcentration of 34-40% in weight, have a viscosity lower than 9-10mPa's at 370° C., when solutions containing mixtures of ionic andnon-ionic iodinated contrast agents are prepared. But as a matter offact, this approach does not overcome the above mentioned difficultiessince the neutralisation of counter-cations is still necessary. Theresults is an increase in osmolality and the osmotic load, despite theacceptable viscosity values possibly obtained.

Other documents which can be cited as a reference to the state of theart are: U.S. Pat. No. 3,701,771, U.S. Pat. No. 4,396,598, U.S. Pat. No.5,019,271, WO 92/09562, WO 92/13636, WO 89/08101, EP 390242, EP 437444,EP 306364. Nevertheless none of them gives a satisfactory answer to theabove disclosed problems.

SUMMARY OF THE INVENTION

This invention provides important and significant advantages in thefield of injectable formulations of iodinated contrast media for X-rayimaging. It was unexpectedly and surprisingly found that injectableaqueous compositions, comprising mixtures of non-ionic iodinatedaromatic compounds monomer of type (a) and dimers of type (b) , not onlyhave an intermediate osmolality compared to the pure solutions of (a)and (b), and are also isoosmolal or isotonic to the plasma but they alsohave a lower viscosity than the expected, and a lower toxicity thanthose shown by the corresponding pure solutions of (a) and (b).Furthermore, during the injection, they supply a favourable iodinedelivery rate through less invasive catheters.

Compounds (a) preferably have a structure as indicated in the followinggeneral formula (I) ##STR1## wherein:

A, B, D, which are the same or different, are --CON(R)R₁ or--N(R)--CO--R₂ groups, wherein

R is H or a linear or branched alkyl residue (C₁ -C₆), optionallysubstituted by 1-5 OH and/or alkoxy and/or hydroxyalkoxy groups,

R₁ is a linear or branched alkyl residue (C2-C₆), optionally substitutedby 1-5 OH and/or alkoxy and/or hydroxyalkoxy groups, or by one of thetwo groups --NH--CO--R₁ or --CO--N (R)R₁, or R₁ is the residue of acarbohydrate, or R₁ and R, taken together, are an alkylene chain (C3-C₇)which can be interrupted by O, S, N,

R₂ is a linear or branched alkyl residue (C1-C₆), optionally substitutedby 1-5 OH and/or alkoxy and/or hydroxyalkoxy groups, and can alsoinclude an oxo group.

Compounds (b) preferably have the following formula (II) ##STR2##wherein:

A, B, D, which are the same or different, have the same meanings offormula I,

E, which are the same or different, are selected among --CO--N(R)--,--N(R)--CO--, --N(COR₃)-- groups where R has the same meanings offormula (I) and R₃ is an alkyl residue (C₁ -C₃) optionally substitutedby 1-2 OH or by alkoxy or hydroxyalkoxy groups,

X is a covalent bond or a linear or branched alkylene chain (C₁ -C₈),which can be substituted by 1-6 OH groups and/or --CO--NHR groups, andwhich can be interrupted by --O--, --S--, --N--, --N(R)--CO groups,being R as above defined in formula (I).

Among monomers of type (a), particularly preferred are those listed inTable 2.

                                      TABLE 2                                     __________________________________________________________________________    Preferred compound of type (a)                                                Generic Name                                                                  (source)                                                                             FORMULA I                                                              CAS  RN!                                                                             A                   B             D                                    __________________________________________________________________________    metrizamide  31112-62-6!                                                              ##STR3##           N(Me)Ac       NHAc                                 iopamidol                                                                            CONHCH(CH.sub.2 OH).sub.2                                                                         CONHCH(CH.sub.2 OH).sub.2                                                                   NHCOCH(OH)CH.sub.3                    60166-93-0!                                                                  iomeprol                                                                             CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                     CONCH.sub.2 CH(OH)CH.sub.2 OH                                                               N(Me)COCH.sub.2 OH                    78649-41-9!                                                                  iopromide  73334-07-3!                                                               CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                      ##STR4##     NHCOCH.sub.2 OMe                     ioversol  877771-40-2!                                                               CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                     CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                ##STR5##                            iohexol  66108-95-0!                                                                 CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                     CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                ##STR6##                            iopentol  89797-00-2!                                                                CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                     CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                ##STR7##                            ioxilan  107793-72-6!                                                                CONCH.sub.2 CH.sub.2 OH                                                                           CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                ##STR8##                            II-1  99139-49-8!                                                                    CONCH.sub.2 CH(OH)CH.sub.2 OH                                                                      ##STR9##                                                                                    ##STR10##                           iogulamide                                                                           CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                                    CONCH.sub.2 CH(OH)CH.sub.2 OH                                                               NHCOCO(CHOH).sub.3 CH.sub.2 OH        75751-89-2!                                                                  ioglucol  63941-73-1!                                                                CONHMe              NHCOCH(OH).sub.4 CH.sub.2 OH                                                                 ##STR11##                           ioglucamide                                                                          CONHMe              NHCOCH(OH).sub.4 CH.sub.2 OH                                                                NHCOCHOH).sub.4 CH.sub.2 OH           63941-74-2!                                                                  ioglunide                                                                            CONHCH.sub.2 CH.sub.2 OH                                                                          NHCOCH(OH).sub.4 CH.sub.2 OH                                                                N(Me)Ac                               56562-79-9!                                                                  MP-7011                                                                              CONHCH.sub.2 (CHOH).sub.5 CH.sub.2 OH                                                             N(Me)Ac       NHAc                                  76984-84-0!                                                                  MP-7012  64965-50-0!                                                                  ##STR12##          N(Me)Ac       NHAc                                 MP-10007                                                                             CONHCH.sub.2 CH.sub.2 OH                                                                          NHCOCO(CHOH).sub.3 CH.sub.2 OH                                                              NHCOCO(CHOH).sub.3 CH.sub.2 OH        77111-65-0!                                                                  VA-7-88  79944-49-3!                                                                  ##STR13##                                                                                         ##STR14##    N(Me)Ac                              (EP 033426)  79944-51-7!                                                              ##STR15##                                                                                         ##STR16##                                                                                   ##STR17##                           iosimide  79211-10-2!                                                                CON(CH.sub.2 CH.sub.2 OH).sub.2                                                                   CON(CH.sub.2 CH.sub.2 OH).sub.2                                                             CON(CH.sub.2 CH.sub.2 OH).sub.2      iocibidol  79211-34-0!                                                                ##STR18##                                                                                         ##STR19##    CONH.sub.2                           (EP 0177414)  103876-29-5!                                                            ##STR20##                                                                                         ##STR21##                                                                                   ##STR22##                             Among dimeric compounds of type (b), particularly preferred are those       listed in Table 3.                                                        

    TABLE 3                                                                       __________________________________________________________________________    Preferred compounds of type (b)                                               Generic Name                                                                  (source)                                                                              FORMULA II                                                            CAS  RN!                                                                              A             BD            EXE                                       __________________________________________________________________________    iofratol  141660-63-1!                                                                CONHCH(CH.sub.2 OH).sub.2                                                                   NHCOCH(OH)CH.sub.3                                                                           ##STR23##                                iodixanol  92339-11-2!                                                                CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                              CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                               ##STR24##                                iotrol  79770-24-4!                                                                    ##STR25##                                                                                   ##STR26##                                                                                   ##STR27##                                iotasul  71767-13-0!                                                                   ##STR28##                                                                                   ##STR29##                                                                                   ##STR30##                                iodecol  81045-33-2!                                                                  CONHCH(CH.sub.2 OH).sub.2                                                                   CONHCH(CH.sub.2 OH).sub.2                                                                    ##STR31##                                (WO 92/08691)  143200-04-8!                                                           CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                              NHCOCH.sub.2 OH                                                                              ##STR32##                                (WO 92/08691)  143199-77-3!                                                           CONHCH(CH.sub.2 OH).sub.2                                                                   NHCOCH.sub.2 OH                                                                              ##STR33##                                (WO 92/08691)  143200-00-4!                                                           CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                              NHCOCH.sub.2 OH                                                                              ##STR34##                                (US 4348377)  78341-84-1!                                                             CONHCH.sub.2 CH(OH)CH.sub.2 OH (B 17500)                                                    CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                               ##STR35##                                (EP 0308364)  122731-47-9!                                                             ##STR36##    CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                               ##STR37##                                (EP 0308364)  122731-49-1!                                                             ##STR38##    CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                               ##STR39##                                (WO 85/01727)  99139-65-8!                                                             ##STR40##                                                                                   ##STR41##    CONHCH.sub.2 CH.sub.2 NHCO                (WO 85/01727)  99139-62-5!                                                             ##STR42##                                                                                   ##STR43##                                                                                   ##STR44##                                (EP 0023992)  78341-84-1!                                                             CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                              CONHCH.sub.2 CH(OH)CH.sub.2 OH                                                               ##STR45##                                __________________________________________________________________________

Particularly preferred contrastographic compositions of this inventioncomprise the following iodinated monomer and dimer mixtures:

iopamidol/iofratol; iomeprol/iofratol; iomeprol/compound A EP 23992 B:Ex.15!; iopamidol/compound A; iohexol/iodixanol; iopromide/iodecol;iopromide/iotrol; iomeprol/iodecol; iomeprol/iodixanol;iopentol/iodixanol and all their combinations.

In the compositions of this invention the respective proportions ofcompounds (a) and (b) can limitlessly vary within the range indicated inthe claims (i.e. (a) and (b) are present in the mixture in such a ratiothat the iodine quantity of (b) can range between 10-90% in weight,preferably between 20-75%, of the total iodine content in thecomposition, while the chosen values basically depend upon the specificdiagnostic use and the desired properties of the injectable preparation.Some of them can be mentioned: iodine concentration, osmolality,viscosity, distribution flow in circulation or in other cavities, timeof retention in the organs to be examined, excretion and ways ofelimination. Specific data concerning the above mentioned parameters arereported in the following experimental examples.

The formulations of this invention, which mixture of opacifying agents(a) and (b) is totally dissolved to give iodine concentrations of200-450 g/L or more, are particularly suitable for the anglographicimaging of small vessels, i.e. in brain and cerebrospinal cavities,requiring a low viscosity contrast liquid injection.

According to the use, viscosity can be kept between 4-12 mPa's, whileosmolality can vary between 50-500 mosmol/kg. It was particularlysurprising that the mixtures of compounds (a) and (b) according to thepresent invention showed a better tolerability--especiallyneurotropic--than the one expected by adding those of the singlecomponents. The reason for this unexpected remarkable advantage has noexplanation yet.

The performance of the compositions of this invention is completed andincreased by the addition of a series of additives, particularlystabilisers, agents controlling the dissolution, buffers (i.e. TRIS) oralso biologically acceptable mineral salts.

The additives of the formulations of this inventions are those commonlyknown and used in the pharmaceutical technique.

As matter of non-limiting example, the following salts and compounds canbe cited as particularly preferred additives: halides, carbonates,bicarbonates, sulphates, Na⁺, Mg₂ ⁺, Ca²⁺, phosphates, tromethamol,EDTA, EDTA CaNa₂, heparin, hirudin, glycerol, polyethyleneglycol,dextran and the like.

During the preparation of the composition of this invention, the variousingredients are preferably gradually diluted into a suitable aqueousmedium. One of the preferred procedure, for example, can be summed up asfollows:

one or more iodinated compounds--monomers and dimers--are dissolved indistilled water in successive portions, with the possible addition ofadditives. The resulting solution is submitted to ultrafiltration byusing a porously calibrated membrane, as described in the followingexamples. Then sterilisation is performed according to the standardmethods used to prepare X-ray injectable contrast medium formulations.

Other aspect s of this invention are more extensively described in thefollowing section.

EXAMPLE 1

An injectable contrastographic composition has been prepared byintroducing into water the following ingredients: 246.3 g of iomeprol(0.324 mol) , 342.2 g of iofratol (0.234 mol), 0.8 g of tromethamol,0.36 g of concentrated HCl. The resulting solution has been firstlydiluted to 1 L and then depyrogenated through ultrafiltration by using acellulose membrane Amicon® Y10 (10000 Dalton) temperature=45±5° C.;loading pressure=5 kg/cm² ; permeate flow rate=55 mL/s !. Then,sterilisation is carried out for 30 min at 120° C. The resultingsolution, containing 300 g of iodine per L, has been labelled as"iomeprol/iofratol 300". In a similar way another solution, labelled as"iomeprol/iofratol 320", has been prepared using 255.6 g of iomeprol(0.366 mol), 373.8 g of iofratol (0.256 mol), 0.79 g of tromethamol and0.38 of concentrated HCl (iodine content=320 g/L).

In addition, two 1 L control solutions have been prepared. Theycontained 0.8 g of tromethamol and 0.36 mg of HCl in addition to thefollowing contrastographic agents:

1° labelled as: "iofratol 300", containing 576.1 g/L of iofratol

2° labelled as: "iomeprol 350", containing 714.4 g/L of iomeprol.

The intracerebral toxicity of the previous solution has been determinedby using mice of both sexes, carrying out the experimental protocoldescribed in J. T. Litchfield et al., Pharmacol. Exp. Ther. 96 (1949),99.

LD₅₀ values, expressed in g (iodine)/kg, were the following:

    ______________________________________                                        iomeprol/iofratol 300                                                                             > 1.5                                                     iomeprol/iofratol 320                                                                             > 1.6                                                     iomeprol 350        = 1.30 (1.18-1.44)                                        iofratol 300        = 0.65 (0.57-0.73)                                        ______________________________________                                    

As clearly shown by the previous data, LD₅₀ values in iomeprol/iofratolmixtures were surprisingly higher than those foreseable from the twocontrol solutions. Unfortunately, the exact values were not determined,since higher volumes could not be technically administered to animals.

EXAMPLE 2

A solution of iomeprol/iofratol 300 (1 L) is prepared according to theprocedure described in Example 1.

This solution has a newtonian hydrodynamic behaviour, a viscosity value(measured at 37° C.) of 6.24 mPa's and osmolality of about 300 mosmol/kg(osmometric method of vapour pressure).

The iodine delivery rate Q (expressed in g of iodine/s) is measured bymeans of a 6 hole, 90-cm pigtail Cordis® 4F catheter at a temperature of37° C. and at a pressure of about 58.5 atm or 5.92 mPa. In the same way,Q values are measured in control solutions of iomeprol 300 and iofratol300. The resulting values are reported in the following table:

    ______________________________________                                                       Q         Osmolality                                           Solution       g (iodine)/s                                                                            (mosmol/kg)                                          ______________________________________                                        iomeprol/      3.79      300                                                  iofratol 300                                                                  iomeprol 300   4.13      517                                                  iofratol 300   3.43      141                                                  ______________________________________                                    

When compared to pure compound solutions, the advantages of the mixtureare striking: osmolality is practically equivalent to blood, while thecatheter flow rate is higher than the pure dimeric and a bit lower thanthe pure monomeric, which is greatly hyperosmolal.

EXAMPLE 3

A solution (1 L) containing a mixture of 178.12 g of iomeprol (0.234mol) and 596.35 g of iofratol (0.408 mol) is prepared according to theprocedure described in Example 1.

The resulting solution (labelled as "iomeprol/iofratol 400") has aiodine content of 400 g (iodine)/L.

The two control solutions are prepared according to the procedure ofExample 1:

"iomeprol 400": 798.95 g of iomeprol in 1 L of solution (400 g(iodine)/L)

"iofratol 400": 767.45 g of iofratol in 1 L of solution (400 g(iodine)/L).

The viscosity of the three solutions is measured at 37° C. by means of aHaake CV100 viscometer. The results obtained (iomeprol/iofratol 400=14.3mPa's; iomeprol 400=13.6 mPa's; iofratol 400=30.8 mPa's) show that themixture viscosity is surprisingly similar to the one of the less viscouscomponent (the monomer), taken alone, and lower than the one calculatedby hypothesizing the contribution of the two components proportional totheir presence in the mixture in molar fraction terms.

EXAMPLE 4

Further compositions were prepared according to the invention, by usingthe pair of compounds hereunder listed, in concentrations that allowedsolutions at a iodine content of about 300 g (iodine)/L. The componentratio has been studied case by case to obtain a osmolal value similar toblood for each formulation.

The following mixtures have been prepared confirming the previouslydiscussed unexpected advantages, in comparison to the solutions of eachsingle component with the same iodine content of the mixture:

iohexol/iodixanol; iopromide/iodecol; iopromide/iotrol;iomeprol/iodecol; iomeprol/iodixanol; iopentol/iodixanol.

We claim:
 1. An aqueous injectable composition, useful to obtain imagesduring X-ray examinations, comprising, dissolved into an aqueous medium,a mixture of:(a) a non-ionic organic compound comprising a triiodinatedaromatic nucleus having, in the remaining positions, linear or branchedfunctionally substituted organic residues, said compound (a) havingformula ##STR46## wherein: A, B, D are the same or different and are--CON(R)R₁ or --N(R)--CO--R₂ groups wherein R is H or a linear orbranched alkyl residue (C₁ -C₆), unsubstituted or substituted by 1-5 OHalkoxy or hydroxyalkoxy groups, or both OH and alkoxy or both OH andhydroxyalkoxy groups, R₁ is a linear or branched alkyl residue (C₁ -C₆),unsubstituted or substituted by 1-5 OH or alkoxy, OH and hydroxyalkoxygroups, or both OH and alkoxy or both OH and hydroxyalkoxy groups, or byone of the groups --NH--CO--R₁ or --CO--N(R)R₁, or R₁ is the residue ofa carbohydrate, or R₁ and R, taken together, are an alkylene chain (C₃-C₇), said alkylene chain being non-interrupted or interrupted by O, S,N, or an oxo group, R₂ is a linear or branched alkyl residue (C₁ -C₆),unsubstituted or substituted by 1-5 OH or alkoxy or hydroxyalkoxygroups, or both OH and alkoxy, OH and hydroxyalkoxy groups, (b) is anon-ionic organic compound comprising at least two triiodinated aromaticnuclei covalently bound together, in one of the non iodine-substitutedpositions through a linear or branched and functionally substitutedorganic residue, said aromatic nuclei being further substituted in theremaining positions by organic residues as defined hereinabove incompound (a), said compound (b) having the formula (II) ##STR47##wherein: A, B, D, are the same or different, and have the same meaningas in formula (I), E, are the same or different, and are a memberselected from the group consisting of --CO--N(R)--, --N(R)--CO--,--N(COR₃)-- wherein R has the same meaning as in formula (I) and R₃ isan alkyl residue (C₁ -C₃) which is unsubstituted or substituted by 1-2OH or by alkoxy or hydroxyalkoxy groups, X is a covalent bond or alinear or branched alkylene chain (C₁ -C₈), which is unsubstituted orsubstituted by 1-6 OH groups or --CO--NHR groups, or both OH and--CO--NHR groups, said alkylene chain being non-interrupted orinterrupted by --O--, --S--, --N--, --N(R)--CO groups, R being the sameas in formula (I),said compounds (a) and (b) being present in saidmixture in such a ratio that the iodine quantity of compound (b) rangesbetween 10 and 90% by weight of the total iodine amount present in thecomposition, and the total iodine amount in the composition ranges from200 to 450 g I/l, said composition further having an osmolality 0.8-1.5times the physiological value and a viscosity ranging from 4 to 12mPa's.
 2. The composition according to claim 1, wherein said compound(a) is a member selected from the group consisting of iopamidol,metrizamide, iodamide, iomeprol, iopromoide, ioversol, ioglunide,iosimide, iohexol, iogulamide and said compound (b) is a member selectedfrom the group consisting of iotrolan, iodixanol, iofratol, 1,3-bis-N-(3,5-bis-(2,3,-dihydroxypropyl-aminocarbonyl)-2,4,6-triiodophenyl)-N-hydroxyacetyl-amino!-propane.3. The composition according to claim 1 which comprises additivesselected from excipients, stabilizers, control agents for dissolution,physiologically tolerable water-soluble mineral salts, wherein saidmineral salts are halides, carbonates, bicarbonates, sulphates,phosphates of Na, K, Mg, Ca and an anticlotting agent which is heparinor hirudin.
 4. The composition according to claim 3 wherein saidexcipients are glycerol, polyethylenglycol or dextran.
 5. Thecomposition according to claim 3 wherein said stabilizers aretromethamol, EDTA, EDTA CaNa₂, or sodium phosphate.